History

Signs and symptoms of carcinoid tumors vary greatly and depend on the location and size of the tumor and on the presence of metastases. Findings range from no tumor-related findings to full symptoms of carcinoid syndrome. Because carcinoid tumors are rare in children, clinicians rely on reports of adult patients to understand the full scope of the manifestations of the disease.

Approximately 80% of appendicial tumors are incidentally discovered during surgery for other indications, but some cause or coexist with acute appendicitis.

Diagnosis and differential diagnosis

Because symptoms can be vague and intermittent, diagnosis may be delayed, especially in children, in whom the tumor is rare and the diagnosis is unexpected.

Diagnostic difficulties may arise in patients who have flushing without a large tumor or metastases and in those without symptoms.

The diagnosis is sometimes made because of unrelated findings, such as anemia, endocrine disease, or autoimmune disease.

Tumors in the chest can produce symptoms because of their location or can be discovered using chest radiography.

In the absence of positive imaging findings and biochemical markers, in the differential diagnoses disorders such as an adverse reaction to medications, other malignant disorders (eg, chronic myelogenous leukemia), mastocytosis, and other tumors should be considered.

The availability of octreotide-receptor scintigraphy allows for the detection of the tumor and metastases. When results are positive, they may also allow for therapy by using octreotide with large doses of therapeutic radioactive agents.

Clinical presentations and symptoms

The most common clinical presentation for a small intestinal carcinoid is periodic abdominal pain, which can be caused by fibrosis of the mesentery, kinking of the bowel, or intestinal obstruction. A constellation of symptoms called malignant carcinoid syndrome is often associated with this tumor.

Production of vasoactive intestinal peptide (VIP) may produce symptoms similar to those of neuroblastoma, which is far more prevalent than carcinoid in children.

Ectopic adrenocorticotropic hormone (ACTH) and Cushing syndrome observed with foregut carcinoid tumors must be differentiated from other tumors that produce these symptoms. Likewise, rare acromegaly caused by the carcinoid tumors must be differentiated from pituitary tumors.

Carcinoid crisis can occur spontaneously or as a response to stress, such as anesthesia or chemotherapy. Symptoms may include intense flushing, diarrhea, abdominal pain, tachycardia, hypertension or hypotension, altered mental status, and coma. This condition can be life threatening, but treatment with somatostatin analog SMS-201-995 has improved the outcome of patients with carcinoid crisis.

An early and frequent (94%) symptom of carcinoid tumors, especially those of midgut with metastases, is cutaneous flushing, which typically affects the head and neck. Striking color changes range from pallor or erythema to cyanosis. Episodes are often associated with an unpleasant warm feeling, itching, palpitation, upper-body erythema and edema, salivation, diaphoresis, lacrimation, and diarrhea. Exercise, stress, or certain foods (eg, cheese) may trigger an attack, although the flushes can also be spontaneous and unrelated to any stimulation. Initial attacks are short, lasting only a few minutes. With time, the duration increases to hours. Flushes are reported to be longest in association with bronchial carcinoids. Some patients develop a constant red or cyanotic discoloration.

Diarrhea and malabsorption occur in as many as 84% of patients. Stools are watery, frothy, bulky, or in the form of steatorrhea. Diarrhea may or may not be associated with abdominal pain, flushing, and cramps. It may be profuse and often colicky.

Wheezing or asthmalike syndrome is caused by bronchial constriction and may occur in as many as 25% of patients. Some tremors are relatively indolent and result in chronic symptoms such as cough, shortness of breath and dyspnea.
[7] Bronchopulmonary carcinoid tumor presenting with Cushing syndrome has been reported.
[34] Behavior of bronchial carcinoid tumor can range from benign to aggressive with metastasis.
[35] A child with a carcinoid tumor who had late relapse in mediastinum and metastasis to cerebellum 16 years after the initial diagnosis with atypical carcinoid tumor has been reported.
[35]

Other symptoms of carcinoid tumors may include valvular heart lesions. Cardiac manifestations are observed in as many as 60% of patients. Fibrosis of the endocardium, which often involves the right side of the heart, is observed. The fibrous deposit usually involves the ventricular aspect of the tricuspid valve and associated chordae. Fibrosis of the pulmonic valve is relatively uncommon and results in regurgitation or stenosis. Cardiac lesions may lead to heart failure. The mitral valve is infrequently involved.

Multicentric tumor involving more than one organ (eg, larynx and thyroid) has been reported.
[37, 38]

A second primary tumor in association GI carcinoids can occur. A case of hepatocellular carcinoma post diagnosis of carcinoid tumor has been reported.
[39] These secondary tumors tend to be aggressive. In all cases of carcinoid tumor, care should be given to evaluate and follow patients for possible second malignancies.

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Causes

The etiology of carcinoid tumors is not known, but genetic abnormalities are suspected. Reported chromosomal abnormalities include changes in chromosomes, such as loss of heterogeneity, and numerical imbalances.

MEN 1 is an autosomal dominant disorder characterized by the occurrence of multiple tumors, particularly in the pancreatic islets, parathyroid and pituitary glands, and neuroendocrine tumors.
[40]

Germline mutations in the MEN 1 gene can be identified in the general population.

Multiple carcinoid tumors occurring in association with MEN 1 have been reported.
[41]

Although the MEN 1 gene locus is known to be involved in neuroendocrine tumors, the genetic events underlying the neoplastic process are basically unknown.

Familial cases other than those associated with MEN 1 are rare, but do occur.
[42]

In several studies, loss of heterozygosity (LOH) at the MEN 1 locus has been reported.
[43, 44, 45, 46, 47, 48]

Genetic abnormalities involving chromosome 11 are most common. These can be seen as a part of MEN 1 or independent of MEN 1 abnormalities.
[47, 48] In 5 of 9 typical carcinoid tumors of the lung, 3 distinct regions of allelic loss were identified at bands 11q13.1 (D11S1883), 11q14.3-11q21 (D11S906), and 11q25 (D11S910).

Some atypical carcinoids have LOH at band 11q13 between markers PYGM and D11S937 and at bands 11q14.3-11q21 (D11S906), 11q23.2-23.3 (D11S939), and 11q25 (D11S910).

The region of band 11q13 bearing the MEN 1 gene can also be affected in some atypical carcinoid tumors more than it is in typical carcinoid tumors. Therefore, band 11q13 appears to be important in these tumors. Aggressive atypical carcinoid tumors, defined by high mitosis, vascular invasion and organ metastasis, also appear to have more allelic losses than other tumors.

The MEN 1 gene is located on band 11q13 and likely functions as a tumor-suppressor gene. In a study of 46 sporadically occurring tumors, 78% had LOH at this site, with almost the entire allele missing in 5 patients. In the remaining cases, genetic heterozygosity had a discontinuous pattern. Some have postulated that sporadically occurring carcinoid tumors evolve after inactivation of a tumor-suppressor gene on chromosome 11 as well as genetic mutations that affect DNA-mismatch repair.

Gastric neuroendocrine tumors are associated with a high incidence of LOH at chromosomal arm 8p and a lowered frequency of LOH at 7q. Chromosomal arm 8p is suspected to be the possible location of the tumor-suppressor gene associated with the genesis of gastric neuroendocrine tumors.

LOH on the X chromosome is seen in 15% of malignant carcinoid tumors.
[45, 46]

Numerical imbalances of chromosomes have been observed in carcinoid tumors.

In one study of midgut carcinoids, numerical changes were found in 16 of the 18 tumors.

The most common aberrations were losses of bands 18q22-qter (67%), 11q22-q23 (33%), and 16q21-qter (22%) with a gain of band 4p14-qter (22%). Rates of alterations were substantially more common in metastases than in primary tumors.

Losses of chromosomal arms 18q and 11q were found in the primary tumors and metastases, whereas loss of 16q and gain of 4p were present only in metastases.

HER2 expression has been reported in intestinal, but not gastric, tumors.
[49]

Some studies have implicated homeobox gene Hoxc6 through activation of the oncogenic activator protein-1 signaling pathway and via interaction with JunD in carcinoid tumorigenesis.
[50] Mutation in the home domain of Hoxc6, which blocks this interaction, results in inhibition of the carcinoid tumor cell proliferation in vitro.

One postulate is that loss of chromosomal arms 18q and 11q may represent an early event and that the loss of 16q and gain of 4p occur as a late event in midgut carcinoids.